WO2008131148A1 - Dérivés de diphényl-hétéroaryle et leur utilisation pour la liaison et l'imagerie de plaques amyloïdes - Google Patents

Dérivés de diphényl-hétéroaryle et leur utilisation pour la liaison et l'imagerie de plaques amyloïdes Download PDF

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WO2008131148A1
WO2008131148A1 PCT/US2008/060710 US2008060710W WO2008131148A1 WO 2008131148 A1 WO2008131148 A1 WO 2008131148A1 US 2008060710 W US2008060710 W US 2008060710W WO 2008131148 A1 WO2008131148 A1 WO 2008131148A1
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alkyl
compound
hydroxy
hydrogen
halogen
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PCT/US2008/060710
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English (en)
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Hank F. Kung
Mei-Ping Kung
Wenchao Qu
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The Trustees Of The University Of Pennsylvania
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Priority to US12/595,131 priority Critical patent/US20110158907A1/en
Priority to JP2010504257A priority patent/JP2010524965A/ja
Priority to EP08746182A priority patent/EP2144507A4/fr
Publication of WO2008131148A1 publication Critical patent/WO2008131148A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to diphenyl-heteroaryl compounds, the uses thereof in diagnostic imaging and inhibiting amyloid- ⁇ aggregation, and methods of making these compounds.
  • AD Alzheimer's disease
  • SPs senile plaques
  • a ⁇ amyloid- ⁇
  • NFTs neurofibrillary tangles
  • Amyloidosis is a condition characterized by the accumulation of various insoluble, fibrillar proteins in the tissues of a patient.
  • An amyloid deposit is formed by the aggregation of amyloid proteins, followed by the further combination of aggregates and/or amyloid proteins. Formation and accumulation of aggregates of ⁇ amyloid (A ⁇ peptides in the brain are critical factors in the development and progression of AD.
  • amyloid deposits In addition to the role of amyloid deposits in Alzheimer's disease, the presence of amyloid deposits has been shown in diseases such as Mediterranean fever, Muckle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amyloid cardiomyopathy, systemic senile amyloidosis, amyloid polyneuropathy, hereditary cerebral hemorrhage with amyloidosis, Down's syndrome, Scrapie, Creutzfeldt- Jacob disease, Kuru, Gerstamnn-Straussler-Scheinker syndrome, medullary carcinoma of the thyroid, Isolated atrial amyloid, ⁇ 2-microglobulin amyloid in dialysis patients, inclusion body myositis, ⁇ 2-amyloid deposits in muscle wasting disease, and Islets of Langerhans diabetes Type II insulinoma.
  • diseases such as Mediterranean fever, Muckle-Wells syndrome, idiopathic myeloma, amyloid polyneuropathy, amy
  • the fibrillar aggregates of amyloid peptides, A ⁇ i_4o and A ⁇ i_4 2 are major metabolic peptides derived from amyloid precursor protein found in senile plaques and cerebrovascular amyloid deposits in AD patients (Xia, W., et al, J. Proc. Natl. Acad. Sci. U.S.A. 97: 9299-9304 (2000)).
  • Prevention and reversal of A ⁇ plaque formation are being targeted as a treatment for this disease (Selkoe, D., J. JAMA 283:1615-1617 (2000); Wolfe, M.S., et al, J. Med. Chem. 41 :6-9 (1998); Skovronsky, D.M., and Lee, V.M., Trends Pharmacol. Sci. 27:161-163 (2000)).
  • Familial AD is caused by multiple mutations in the A precursor protein (APP), presenilin 1 (PSl) and presenilin 2 (PS2) genes (Ginsberg, S. D., et al., "Molecular Pathology of Alzheimer's Disease and Related Disorders," in Cerebral Cortex: Neurodegenerative and Age- related Changes in Structure and Function of Cerebral Cortex, Kluwer Academic/Plenum, NY (1999), pp. 603-654; Vogelsberg-Ragaglia, V., et al, "Cell Biology of Tau and Cytoskeletal Pathology in Alzheimer's Disease,” Alzheimer's Disease, Lippincot, Williams & Wilkins, Philadelphia, PA (1999), pp. 359-372).
  • APP A precursor protein
  • PSl presenilin 1
  • PS2 presenilin 2
  • AD pathogenesis (Selkoe, D. J., "Biology of ⁇ -amyloid Precursor Protein and the Mechanism of Alzheimer's Disease,” Alzheimer's Disease, Lippincot Williams & Wilkins, Philadelphia, PA (1999), pp. 293-310; Selkoe, D.
  • the inhibition constants (K 1 ) for binding to fibrillar A ⁇ aggregates of CR, CG, and 3'-bromo- and 3'-iodo derivatives of CG are 2,800, 370, 300 and 250 nM, respectively (Mathis, C. A., et al, Proc. XIIth Intl. Symp. Radiopharm. Chem., Uppsala, Sweden:94-95 (1997)).
  • These compounds have been shown to bind selectively to A ⁇ (1-40) peptide aggregates in vitro as well as to fibrillar A ⁇ deposits in AD brain sections (Mathis, C. A., et al, Proc. XIIth Intl. Symp. Radiopharm. Chem., Uppsala, Sweden:94-95 (1997)).
  • a ⁇ aggregates in the brain There are several potential benefits of imaging A ⁇ aggregates in the brain.
  • the imaging technique will improve diagnosis by identifying potential patients with excess A ⁇ plaques in the brain; therefore, they may be likely to develop Alzheimer's disease. It will also be useful to monitor the progression of the disease.
  • imaging A ⁇ plaques in the brain may provide an essential tool for monitoring treatment.
  • a simple, noninvasive method for detecting and quantitating amyloid deposits in a patient has been eagerly sought.
  • detection of amyloid deposits involves histological analysis of biopsy or autopsy materials. Both methods have drawbacks. For example, an autopsy can only be used for a postmortem diagnosis.
  • amyloid deposits in vivo are difficult, as the deposits have many of the same physical properties (e.g., density and water content) as normal tissues. Attempts to image amyloid deposits using magnetic resonance imaging (MRI) and computer-assisted tomography (CAT) have been disappointing and have detected amyloid deposits only under certain favorable conditions. In addition, efforts to label amyloid deposits with antibodies, serum amyloid P protein, or other probe molecules have provided some selectivity on the periphery of tissues, but have provided for poor imaging of tissue interiors. Potential ligands for detecting A ⁇ aggregates in the living brain must cross the intact blood-brain barrier. Thus brain uptake can be improved by using ligands with relatively smaller molecular size (compared to Congo Red) and increased lipophilicity.
  • [ ⁇ C]6-OH-BTA-l retention was increased most prominently in the frontal cortex. Large increases also were observed in parietal, temporal, and occipital cortices and in the striatum. [ ⁇ C]6-0H-BTA-l retention was equivalent in AD patients and comparison subjects in areas known to be relatively unaffected by amyloid deposition (such as subcortical white matter, pons, and cerebellum). Recently, another 11 C labeled A ⁇ plaque -targeting probe, a stilbene derivative- [ 11 C]SB- 13, has been studied.
  • the present invention provides novel compounds of Formulae I, I', II, I" and I'".
  • the present invention also provides diagnostic compositions comprising radiolabeled compounds of Formulae I, I', II, I" and I'" and a pharmaceutically acceptable carrier or diluent.
  • the invention further provides methods of imaging amyloid deposits, the methods comprising introducing into a patient a detectable quantity of a labeled compound of Formulae I, I', II, I" or I'” or a pharmaceutically acceptable salt, ester, amide or prodrug thereof.
  • the present invention also provides methods for inhibiting the aggregation of amyloid proteins, the methods comprising administering to a mammal an amyloid inhibiting amount of a compound of Formulae I, I', II, I" or I'" or a pharmaceutically acceptable salt, ester, amide, or prodrug thereof.
  • a further aspect of this invention is directed to methods and intermediates useful for synthesizing the amyloid inhibiting and imaging compounds of Formulae I, I', II, I" and I'" described herein.
  • Fig. 1 depicts preferred triazole embodiments of the present invention.
  • Fig. 2 depicts preferred triazole embodiments of the present invention and certain of their respective binding data.
  • Fig. 3 depicts HPLC profiles of preferred embodiments of the present invention.
  • HPLC condition Agilent 1100 series; Gemini C- 18 analytical column (4.6 x 250 mm, 5 mm),
  • Fig. 4 depicts brain uptakes and washouts of preferred embodiments of preferred radiolabeled triazole probes of the present invention in normal mice.
  • Fig. 5 depicts in vitro film autoradiography of macroarray brain sections constructed from AD and control cases.
  • the A ⁇ plaques were clearly visualized with low background labeling with two preferred radio fluorinated probes of the present invention. High white matter labeling was observed with the iodinated probe, in addition to plaque labeling.
  • Fig. 6 depicts specific binding of preferred embodiments of the present invention to pooled AD and control brain tissue homogenates. Gray and white matters were dissected from the cortical regions. Higher specific binding was detected mainly in gray matter of AD. Relatively low binding was measured in white matter homogenates of AD as well as in gray and white matter homogenates of the control brain.
  • Fig. 7. depicts the Standardized Uptake Value (nCi/cc/mCi injected) of one embodiment of the present invention in cortical matter regions (open circles) and white matter regions (closed circles) of the rhesus monkey brain versus time post injection. Very fast and high uptake is seen in the cortex with rapid washout, along with low non-specific binding and washout in white matter regions
  • W, Y and Z are each independently CH, N, NH, O or S; provided that at least one of W, Y and Z is N or O;
  • V and X are independently C or N;
  • a 1 and A 2 are independently N, CR 3 or CR 4 as permitted;
  • R 1 and R 2 are independently:
  • R a and R b are independently hydrogen, (C 1 . 4)alkyl, hydroxy(Ci_ 4 )alkyl or halo(Ci_ 4 )alkyl, and p is an integer from 0 to 5; hydroxy; (Ci_ 4 )alkoxy; hydroxy(Ci_ 4 )alkyl; halogen; cyano; hydrogen; nitro; (Ci-C 4 )alkyl; halo(Ci-C 4 )alkyl; fo ⁇ nyl; -NHC0(Ci_ 4 alkyl); -OCO(C M alkyl); or radiohalogen;
  • R 3 is hydrogen or i-vi as shown below:
  • R x and R y are hydrogen, hydroxy or (Ci_ 4 )alkyl; t is 0, 1, 2 or 3; Z is halogen, hydroxy, OTs (tosylate) or amino; and R 30 , R 31 , R 32 and R 33 are in each instance independently hydrogen, hydroxy, (Ci_ 4 )alkoxy, (Ci_ 4 )alkyl, or hydroxy(Ci_ 4 )alkyl;
  • R x and R y are hydrogen, hydroxy or (Ci_ 4 )alkyl; t is 0, 1, 2 or 3; Y is halogen, halogen substituted benzoyloxy, halogen substituted phenyl(Ci_ 4 )alkyl, halogen substituted aryloxy, or halogen substituted (C 6 -io)aryl; U is hydrogen, hydroxy, halogen, halogen substituted benzoyloxy, halogen substituted phenyl(Ci_ 4 )alkyl, halogen substituted aryloxy, or halogen substituted (Ce-io)aryl; and R 34 , R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are in each instance independently hydrogen, halogen, hydroxy, (Ci_ 4 )alkoxy, (Ci_ 4 )alkyl, or hydroxy(Ci_ 4 )alkyl;
  • R 4 is hydrogen, halogen, radiohalogen or -(C 1-4 alkyl) 3 Sn, preferably (Bu) 3 Sn; iii. NRR", wherein at least one of R' and R" is (CH 2 )dX, where X is halogen, preferably F or 18 F, and d is an integer from 1 to 4; the other of R and R" is hydrogen, (Ci_ 4 )alkyl, halo(Ci_ 4 )alkyl, and hydroxy(Ci_ 4 )alkyl; iv.
  • R' and R" is (CH 2 ) d X, where X is halogen, preferably F or 18 F, and d is an integer from 1 to 4; the other of R and R" is hydrogen, (Ci_ 4 )alkyl, halo(Ci_ 4 )alkyl, or hydroxy(Ci_ 4 )alkyl; v. halo(Ci_ 4 )alkyl; or vi. an ether (R-O-R) having the following structure: [halo(Ci_4)alkyl-O-(Ci_ 4)alkyl]-; provided that one of R 3 and R 4 is other than hydrogen.
  • Preferred compounds include those where the halogen, in one or more occurrence on the structure, is a radiolabeled halogen. Also preferred are compounds wherein the halogen is I, 123 I, 125 I, 131 I, Br, 76 Br, 77 Br, F or 18 F. Especially preferred compounds are those that contain 18 F. Compounds containing 123 I are also especially preferred.
  • R 1 and R 2 Useful values of R 1 and R 2 are listed above.
  • one of R 1 and R 2 is hydrogen.
  • Other preferred values are hydroxy or NR a R b (CH2) p -, wherein p is an integer from 0 to 5, and R a and R b are independently hydrogen, Ci_4 alkyl or (CH2)dX, where X is halogen, and d is an integer from 1 to 4
  • Useful values of p include integers from 0 to 5.
  • p is 0, 1 or 2.
  • p is 0 such that R 1 or R 2 represents NR a R b .
  • R 1 is other than hydrogen and is either in the meta or para position relative to the respective bridge.
  • R 1 is NR a R b , wherein R a and R b are independently hydrogen or (Ci_ 4 )alkyl. In this embodiment, it is preferable that the (Ci_ 4 )alkyl is methyl. Preferably one of R a and R b is hydrogen, the other is (Ci_ 4 )alkyl, such as methyl. Most preferably, both R a and R b are methyl. Another preferred value of R 1 is hydroxy. Also preferred are any prodrug groups that after administration yield a preferred value of R 1 . Such prodrug groups are well-known in the art.
  • Useful values of R 3 include substructures i, ii, iii, iv, v, and vi, as depicted above. In preferred embodiments of Formula I, R 3 is either in the meta or para position relative to the respective bridge. Preferably, R 3 is substructure i or ii. In these embodiments, useful values of q include integers from one to ten. Preferably, in a compound where R 3 is i, q is an integer from 1 to 5. Most preferably, q is 1 to 4, especially 1 to 3.
  • useful values of R 30 , R 31 , R 32 and R 33 independently include hydrogen, hydroxy, Ci_4 alkoxy, Ci_4 alkyl, and hydroxy(Ci_ 4)alkyl. Preferred compounds include those where one or more of R 30 , R 31 , R 32 and R 33 are hydrogen. More preferred compounds include those where each of R 30 , R 31 , R 32 and R 33 is hydrogen.
  • Compounds of Formula I include those compounds of the following structure:
  • Preferred compounds of formula I' are those where one of R 1 and R 2 is hydroxy, - OCO(Ci_ 4 alkyl), mono(Ci_ 4 alkyl)amino, di(Ci_ 4 alkyl)amino or -NHCO(Ci_ 4 alkyl), and the other of R 1 and R 2 is hydrogen.
  • Preferred compounds of Formula I' are those where R 4 is hydrogen, radiohalogen or halogen.
  • Preferred compounds of formula I' are those where R is hydrogen or fragment ii. Examples of preferred compounds include:
  • the present invention is directed to compounds of Formula II, having the following structure:
  • W, Y and Z are each independently CH, N, NH, O or S; provided that at least one of W, Y and Z is N or O;
  • V and X are independently C or N;
  • a 1 and A 2 are independently N, CR 13 or CR 14 as permitted;
  • R 11 and R 12 are independently:
  • R a and R b are independently hydrogen, (C 1 . 4)alkyl, hydroxy(Ci_ 4 )alkyl or halo(Ci_ 4 )alkyl, and p is an integer from 0 to
  • R x and R y are hydrogen, hydroxy or (Ci_ 4 )alkyl; t is 0, 1, 2 or 3; and Z, R 30 , R 31 , R 32 and R 33 are as described; and Z is -Ch;
  • Z is -Ch, R 30 , R 31 , R 32 and R 33 are as described above, and wherein R x and R y are hydrogen, hydroxy or (Ci_ 4 )alkyl; t is 0, 1, 2 or 3; Y is -Ch; U is hydrogen, hydroxy, halogen, halogen substituted benzoyloxy, halogen substituted phenyl(Ci_ 4 )alkyl, halogen substituted aryloxy, or halogen substituted (Ce-io)aryl; and R 34 , R 35 , R 36 , R 37 , R 38 , R 39 and R 40 are in each instance independently hydrogen, halogen, hydroxy, (Ci_ 4 )alkoxy, (Ci_ 4 )alkyl, or hydroxy(Ci_ 4 )alkyl; iv.
  • -Ch is a chelating ligand capable of complexing with a metal to form a metal chelate.
  • ligands are known in the art and are suitable for use as a labeling moiety for the compounds of the present invention. Those of skill in the art will understand that such ligands provide a way to label compounds and the invention is not limited to particular ligands, many of which are interchangeable.
  • this ligand is a tri- or tetradentate ligand, such as N 3 , N 2 S, NS 2 , N4 and those of the N 2 S 2 type, represented by, but not limited to, the following structure:
  • R p is hydrogen or a sulfhydryl protecting group
  • R 9 R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 43 and R 44 are in each instance independently hydrogen, hydroxy, amino, methylamino, dimethylamino, (Ci_4)alkoxy, (Ci_4)alkyl, and hydroxy(Ci_4)alkyl.
  • a metal such as 99m-Tc
  • a rhenium radioisotope can be complexed with the tetradentate ligand, rather than technetium.
  • R p are both hydrogen, or can be any of the variety of protecting groups available for sulfur, including methoxymethyl, methoxyethoxymethyl, /?-methoxybenzyl or benzyl. Sulfur protecting groups are described in detail in Greene, T. W. and Wuts, P.G.M., Protective Groups in Organic
  • R P can be removed by appropriate methods well known in the art of organic synthesis, such as trifluoroacetic acid, mercuric chloride or sodium in liquid ammonia. In the case of Lewis acid labile groups, including acetamidomethyl and benzamidomethyl, R p can be left intact. Labeling of the ligand with technetium in this case will cleave the protecting group, rendering the protected diaminedithiol equivalent to the unprotected form. Further, several ligands of the general N 2 S 2 type are known, and can be used interchangeably without changing the scope of the invention; and
  • R 11 or R 12 are hydroxy or NR a R b (CH 2 ) p -, wherein p is an integer from 0 to 5, and R a and R b are independently hydrogen, (Ci_4)alkyl or (CH 2 )dX, where X is halogen, and d is an integer from 1 to 4.
  • Useful values of p include integers from 0 to 5.
  • p is 0, 1 or 2.
  • R 11 is other than hydrogen and is either in the meta or para position relative to the respective bridge.
  • R 11 is NR a R b , wherein R a and R b are independently hydrogen or (Ci_ 4 )alkyl. In this embodiment, it is preferable that the (Ci_ 4 )alkyl is methyl.
  • R a and R b is hydrogen, the other is (Ci_ 4 )alkyl, such as methyl or both R a and R b are methyl.
  • Another preferred value of R 11 is hydroxy.
  • R 11 are any groups that after administration into the body metabolize or degrade to the preferred values of R 11 listed above. Such groups are known in the art to constitute a prodrug and the groups capable of forming prodrugs are well-known to one of ordinary skill in the art.
  • R 13 Useful values of R 13 include substructures i, ii, iii, iv, v and vi as depicted above. In preferred embodiments of Formula I, R 13 is either in the meta or para position relative to the respective bridge. Preferably, in a compound where R 13 is i, q is an integer from 2 to 5. Most preferably, q is 3 or 4.
  • useful values of R 30 , R 31 , R 32 and R 33 independently include hydrogen, hydroxy, (Ci_4)alkoxy, (Ci_4)alkyl, and hydroxy(Ci_4)alkyl. Preferred compounds include those where one or more of R 30 , R 31 , R 32 and R 33 are hydrogen. More preferred compounds include those where each of R 30 , R 31 , R 32 and R 33 is hydrogen.
  • R 4 is a halogen or radiohalogen. More preferably, R 4 is a radiohalogen.
  • Non- limiting examples of compounds of Formula I" are those that contain a monosubstituted phenyl or heteroaryl, such as compound 10b described herein, which is monosubstituted with an iodine.
  • R 1 , R 2 , R 4 , A 1 and A 2 are as described under Formula I.
  • R 3 is ii.
  • Non-limiting examples of compounds of Formula I'" are compounds 15b, 16b and 17b described herein.
  • the compounds have the following general structure wherein there is at least one carbon- carbon bond between a substituent and the ring to which -(CR x R y ) t is bound:
  • the compounds of the present invention can also contain a radioactive isotope of carbon as the radiolabel.
  • a radioactive isotope of carbon refers to a compound that comprises one or more radioactive carbon atoms, preferably 11 C, with a specific activity above that of the background level for that atom.
  • naturally occurring elements are present in the form of varying isotopes, some of which are radioactive isotopes.
  • the radioactivity of the naturally occurring elements is a result of the natural distribution or abundance of these isotopes, and is commonly referred to as a background level.
  • the carbon labeled compounds of the present invention have a specific activity that is higher than the natural abundance, and therefore above the background level.
  • the composition claimed herein comprising a carbon-labeled compound(s) of the present invention will have an amount of the compound such that the composition can be used for tracing, imaging, radiotherapy, and the like.
  • a halogen preferably 18 F, or a chelating agent is linked to the backbone through a PEG chain, having a variable number of ethoxy groups.
  • the compounds of Formulae I, I', II, I" and I'" may also be solvated, especially hydrated. Hydration may occur during manufacturing of the compounds or compositions comprising the compounds, or the hydration may occur over time due to the hygroscopic nature of the compounds.
  • the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.
  • alkyl refers to both straight and branched chain radicals of up to 8 carbons, preferably 6 carbons, more preferably 4 carbons, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and isobutyl.
  • alkoxy is used herein to mean a straight or branched chain alkyl radical, as defined above, unless the chain length is limited thereto, bonded to an oxygen atom, including, but not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
  • the alkoxy chain is 1 to 6 carbon atoms in length, more preferably 1-4 carbon atoms in length.
  • dialkylamine as employed herein by itself or as part of another group refers to an amino group which is substituted with two alkyl groups as defined above.
  • halo or halogen employed herein by itself or as part of another group refers to chlorine, bromine, fluorine or iodine and their isotopes.
  • radiohalogen refers specifically to radioactive halogen isotopes.
  • haloalkyl refers to any of the above alkyl groups substituted by one or more chlorine, bromine, fluorine or iodine with fluorine and chlorine being preferred, such as chloromethyl, iodomethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and 2- chloroethyl.
  • alkylthio as employed herein by itself or as part of another group refers to a thioether of the structure: R-S, wherein R is a Ci_4 alkyl as defined above.
  • alkylsulfonyl as employed herein by itself or as part of another group refers to a sulfone of the structure: R-SO 2 , wherein R is a Ci_4 alkyl as defined above.
  • aryl as employed herein by itself or as part of another group refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl.
  • heterocycle or “heterocyclic ring”, as used herein except where noted, represents a stable 5- to 7- membered mono-heterocyclic ring system which may be saturated or unsaturated, and which consists of carbon atoms and from one to three heteroatoms selected from the group consisting of N, O, and S, and wherein the nitrogen and sulfur heteroatom may optionally be oxidized.
  • rings contain one nitrogen combined with one oxygen or sulfur, or two nitrogen heteroatoms.
  • heterocyclic groups include piperidinyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazinyl, imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, homopiperidinyl, homopiperazinyl, pyridazinyl, pyrazolyl, and pyrazolidinyl, most preferably thiamorpholinyl, piperazinyl, and morpholinyl.
  • heteroatom is used herein to mean an oxygen atom ("O"), a sulfur atom (“S”) or a nitrogen atom (“N”). It will be recognized that when the heteroatom is nitrogen, it may form an NRR moiety, wherein the R groups independently from one another may be hydrogen or Ci_ 4 alkyl, C 2 - 4 aminoalkyl, Ci_ 4 halo alkyl, halo benzyl, or R 1 and R 2 are taken together to form a 5- to 7-member heterocyclic ring optionally having O, S or NR C in said ring, where R c is hydrogen or C 1-4 alkyl.
  • heteroaryl refers to groups having 5 to 14 ring atoms; 6, 10 or 14 IT electrons shared in a cyclic array; and containing carbon atoms and 1, 2, 3 or 4 oxygen, nitrogen or sulfur heteroatoms (where examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4
  • aralkyl or "arylalkyl” as employed herein by itself or as part of another group refers to Ci_ 6 alkyl groups as discussed above having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
  • aryl substituent such as benzyl, phenylethyl or 2-naphthylmethyl.
  • Preferable values under the scope Of C 6-10 aryl include phenyl, naphthyl or tetrahydronaphthyl.
  • Preferable values of under the scope of heteroaryl include thienyl, furyl, pyranyl, pyrrolyl, pyridinyl, indolyl, and imidazolyl.
  • heterocycle Preferable values under the scope of heterocycle include piperidinyl, pyrrolidinyl, and morpholinyl.
  • Another aspect of this invention is related to methods of preparing compounds of Formulae I, T, II, I" and I"'.
  • Some of the advantages of using the chemistry described herein to assemble probes targeting A ⁇ plaques are: 1) synthesis can be broken down to fragments and a key assembling step; 2) this reaction can be adapted to fragments with various substitution groups, therefore, facilitate the assembling of diversified groups of substituting groups; 3) the core structure (such as a tricyclic ring system of diphenyltriazole) contains three nitrogens, which reduce the lipophilicity as compared to the comparable thiophene analogs; 4) additional variation of the triazole ring, containing combinations of an assortment of nitrogen and oxygen atoms may further extend the range of five-member rings suitable for providing probes with high binding affinity; 5) various substitution groups on the tricyclic ring systems may provide a readily prepared probes to modulate the biological kinetics leading to improved signal to noise ratios by PET or SPECT imaging.
  • the desired diphenyltriazole derivatives 15a-b were prepared by a modified one-pot two-step approach, which was developed by Liang et al. In this reaction a chelating ligand trans- ⁇ /,N'-dimethyl-l,2-cyclohexanediamine, copper(I) iodide and an equal amount of sodium ascorbate were used as the catalyts, the desired reactions were accomplished at room temperature in 3 h, the yields of reactions were 99% and 92%, respectively. The alcohols 15a-b were then converted to the tosylates 17a-b (96% and 90%), a microwave-assisted fluorination reaction afforded final products 17a-b (80% and 99%).
  • Tc-99m complexes can be prepared as follows. A small amount of non-radiolabeled compound (1-2 mg) is dissolved in 100 ⁇ L EtOH and mixed with 200 ⁇ L HCl (1 N) and 1 mL Sn-glucoheptonate solution (containing 8-32 ⁇ g SnCl 2 and 80-320 ⁇ g Na-glucoheptonate, pH 6.67) and 50 ⁇ L EDTA solution (0.1 N). [ 99m Tc]Pertechnetate (100-200 ⁇ L; ranging from 2-20 mCi) saline solution are then added. The reaction is heated for 30 min at 100 0 C, then cooled to room temperature. The reaction mixture is analyzed on TLC (EtOHxonc. NH3 9: 1) for product formation and purity check. The mixture can be neutralized with phosphate buffer to pH 5.0.
  • the present invention further relates to a method of preparing a technetium-99m complex according to the present invention by reacting technetium-99m in the form of a pertechnetate in the presence of a reducing agent and optionally a suitable chelator with an appropriate Ch- containing compound.
  • the reducing agent serves to reduce the Tc-99m pertechnetate which is eluted from a molybdenum-technetium generator in a physiological saline solution.
  • Suitable reducing agents are, for example, dithionite, formamidine sulphinic acid, diaminoethane disulphinate or suitable metallic reducing agents such as Sn(II), Fe(II), Cu(I), Ti(III) or Sb(III). Sn(II) has proven to be particularly suitable.
  • technetium-99m is reacted with an appropriate compound of the invention as a salt or in the form of technetium bound to comparatively weak chelators.
  • the desired technetium-99m complex is formed by ligand exchange.
  • suitable chelators for the radionuclide are dicarboxylic acids, such as oxalic acid, malonic acid, succinic acid, maleic acid, orthophtalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or derivatives of these acids; phosphorus compounds such as pyrophosphates; or enolates.
  • Citric acid, tartaric acid, ascorbic acid, glucoheptonic acid or a derivative thereof are particularly suitable chelators for this purpose, because a chelate of technetium-99m with one of these chelators undergoes the desired ligand exchange particularly easily.
  • the N 2 S 2 ligands are usually air-sensitive (thiols are easily oxidized by air) and there are subsequent reactions which lead to decomposition of the ligands.
  • the most convenient and predictable method to preserve the ligands is to produce lyophilized kits containing 100-500 ⁇ g of the ligands under argon or nitrogen.
  • the compounds of this invention When the compounds of this invention are to be used as imaging agents, they must be labeled with suitable radioactive halogen isotopes.
  • 125 I-isotopes are useful for laboratory testing, they will generally not be useful for actual diagnostic purposes because of the relatively long half-life (60 days) and low gamma-emission (30-65 Kev) of 125 I.
  • the isotope 123 I has a half life of thirteen hours and gamma energy of 159 KeV, and it is therefore expected that labeling of ligands to be used for diagnostic purposes would be with this isotope.
  • Other isotopes which may be used include 131 I (half life of 2 hours).
  • Suitable bromine isotopes include 77 Br and 76 Br.
  • Kits for forming the imaging agents can contain, for example, a vial containing a physiologically suitable solution of an intermediate of Formulae I, I', II, I" and I'" in a concentration and at a pH suitable for optimal complexing conditions.
  • the user would add to the vial an appropriate quantity of the radioisotope, e.g., Na 123 I, and an oxidant, such as hydrogen peroxide.
  • the resulting labeled ligand may then be administered intravenously to a patient, and receptors in the brain imaged by means of measuring the gamma ray or photo emissions therefrom.
  • the present invention also relates to a kit, comprising:
  • a non-radiolabeled compound of the invention the compound optionally being in a dry condition; and also optionally having an inert, pharmaceutically acceptable carrier and/or auxiliary substances added thereto; and (2) a reducing agent and optionally a chelator; wherein ingredients (1) and (2) may optionally be combined; and further wherein instructions for use with a prescription for carrying out the above- described method by reacting ingredients (1) and (2) with technetium-99m in the form of a pertechnetate solution may be optionally included.
  • suitable reducing agents and chelators for the above kit have been listed above.
  • the pertechnetate solution can be obtained by the user from a molybdenum-technetium generator. Such generators are available in a number of institutions that perform radiodiagnostic procedures.
  • the ingredients (1) and (2) may be combined, provided they are compatible.
  • Such a monocomponent kit, in which the combined ingredients are preferably lyophilized, is excellently suitable to be reacted by the user with the pertechnetate solution in a simple manner.
  • the radioactive diagnostic agent may contain any additive such as pH controlling agents (e.g., acids, bases, buffers), stabilizers (e.g., ascorbic acid) or isotonizing agents (e.g., sodium chloride).
  • pH controlling agents e.g., acids, bases, buffers
  • stabilizers e.g., ascorbic acid
  • isotonizing agents e.g., sodium chloride
  • pharmaceutically acceptable salt refers to those carboxylate salts or acid addition salts of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively nontoxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts derived from non-toxic organic acids such as aliphatic mono and dicarboxylic acids, for example acetic acid, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids.
  • aliphatic mono and dicarboxylic acids for example acetic acid, phenyl-substituted alkanoic acids, hydroxy alkanoic and alkanedioic acids, aromatic acids, and aliphatic and aromatic sulfonic acids.
  • These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Further representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts, propionate, pivalate, cyclamate, isethionate, and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, and the like
  • nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like See, for example, Berge S. M., et al, Pharmaceutical Salts, J. Pharm. Sci. 66:1-19 (1977) which is incorporated herein by reference.
  • a labeled compound of Formulae I, I', II, I" and I'" is introduced into a tissue or a patient in a detectable quantity.
  • the compound is typically part of a pharmaceutical composition and is administered to the tissue or the patient by methods well known to those skilled in the art.
  • the administration of the labeled compound to a patient can be by a general or local administration route.
  • the compound can be administered either orally, rectally, parenterally (intravenous, by intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (powders, ointments or drops), or as a buccal or nasal spray.
  • the labeled compound may be administered to the patient such that it is delivered throughout the body.
  • the labeled compound can be administered to a specific organ or tissue of interest. For example, it is desirable to locate and quantitate amyloid deposits in the brain in order to diagnose or track the progress of Alzheimer's disease in a patient.
  • One of the most desirable characteristics of an in vivo imaging agent of the brain is the ability to cross the intact blood-brain barrier after a bolus iv injection.
  • the labeled compound is introduced into a patient in a detectable quantity and after sufficient time has passed for the compound to become associated with amyloid deposits, the labeled compound is detected noninvasively inside the patient.
  • a radiolabeled compound of Formula I, I', II, I" or I'" is introduced into a patient, sufficient time is allowed for the compound to become associated with amyloid deposits, and then a sample of tissue from the patient is removed and the labeled compound in the tissue is detected apart from the patient.
  • a tissue sample is removed from a patient and a labeled compound of Formula I, I', II, I" or I'" is introduced into the tissue sample. After a sufficient amount of time for the compound to become bound to amyloid deposits, the compound is detected.
  • tissue means a part of a patient's body. Examples of tissues include the brain, heart, liver, blood vessels, and arteries.
  • a detectable quantity is a quantity of labeled compound necessary to be detected by the detection method chosen.
  • the amount of a labeled compound to be introduced into a patient in order to provide for detection can readily be determined by those skilled in the art. For example, increasing amounts of the labeled compound can be given to a patient until the compound is detected by the detection method of choice.
  • a label is introduced into the compounds to provide for detection of the compounds.
  • patient means humans and other animals. Those skilled in the art are also familiar with determining the amount of time sufficient for a compound to become associated with amyloid deposits.
  • the amount of time necessary can easily be determined by introducing a detectable amount of a labeled compound of Formula I, I', II, I" or I'" into a patient and then detecting the labeled compound at various times after administration.
  • the term "associated” means a chemical interaction between the labeled compound and the amyloid deposit. Examples of associations include covalent bonds, ionic bonds, hydrophilic-hydrophilic interactions, hydrophobic-hydrophobic interactions, and complexes.
  • MRI magnetic resonance imaging
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • the label that is introduced into the compound will depend on the detection method desired. For example, if PET is selected as a detection method, the compound must possess a positron-emitting atom, such as 11 C or 18 F.
  • the radioactive diagnostic agent should have sufficient radioactivity and radioactivity concentration which can assure reliable diagnosis. For instance, in case of the radioactive metal being technetium-99m, it may be included usually in an amount of 0.1 to 50 mCi in about 0.5 to 5.0 ml at the time of administration.
  • the amount of a compound of Formulae I, I', II, I" or I'" may be such as sufficient to form a stable chelate compound with the radioactive metal.
  • the thus formed chelate compound as a radioactive diagnostic agent is sufficiently stable, and therefore it may be immediately administered as such or stored until its use.
  • the radioactive diagnostic agent may contain any additive such as pH controlling agents (e.g., acids, bases, buffers), stabilizers (e.g., ascorbic acid) or isotonizing agents (e.g., sodium chloride).
  • pH controlling agents e.g., acids, bases, buffers
  • stabilizers e.g., ascorbic acid
  • isotonizing agents e.g., sodium chloride
  • Preferred compounds for imaging include a radioisotope such as 11 C, 123 I, 125 I, 131 I, 18 F, 76 Br or 77 Br.
  • Another aspect of the invention is a method of inhibiting amyloid plaque aggregation.
  • the present invention also provides a method of inhibiting the aggregation of amyloid proteins to form amyloid deposits, by administering to a patient an amyloid inhibiting amount of a compound of the above Formulae I, I', II, I" or I'".
  • an amyloid inhibiting amount by simply administering a compound of Formulae I, I', II, I" or I'" to a patient in increasing amounts until the growth of amyloid deposits is decreased or stopped.
  • the rate of growth can be assessed using imaging as described above or by taking a tissue sample from a patient and observing the amyloid deposits therein.
  • the compounds of the present invention can be administered to a patient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is sufficient. The specific dosage used, however, can vary.
  • the dosage can depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used.
  • the determination of optimum dosages for a particular patient is well known to those skilled in the art.
  • the following examples are illustrative, but not limiting, of the method and compositions of the present invention.
  • Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention. All reagents used were commercial products and were used without further purification unless otherwise indicated. Flash chromatography (FC) was performed using silica gel 60 (230- 400 mesh, Sigma- Aldrich).
  • PTLC thin layer chromatography
  • standard workup refers to the following steps: addition of the indicated organic solvent, washing the organic layer with water then brine, separation of the organic layer from the aqueous layer, drying off the combined organic layers with sodium sulfate or magnesium sulfate, filtering off the solid and concentrating the filtrate under reduced pressure.
  • 1 H NMR spectra were obtained at 200 MHz and 13 C NMR spectra were recorded at 50 MHz (Bruker DPX spectrometer). Chemical shifts were reported as lvalues (parts per million) relative to internal TMS.
  • Alkyne 8a (0.042 g, 0.32 mmol), azide 9 (0.32 mmol, 0.079 g) and sodium ascorbate (0.16 mL, fresh prepared 1.0 M solution) were added into tert-butanol/ ⁇ 2 ⁇ (1/1, 2 mL) and the whole mixture was degassed with nitrogen for 10 min. Copper(II) sulfate (CuSO 4 , 1.0 M aqueous solution, 16 ⁇ L) was added and the reaction mixture was vigorously stirred at room temperature (r.t.) for 24 h. After diluted with ice-cold water (10 mL), the mixture was filtered and washed with cold water and ice-cold Et 2 O.
  • CuSO 4 Copper(II) sulfate
  • compound 10b was prepared from alkyne 8b (0.073 g, 0.50 mmol) and 9 (0.147 g, 0.60 mmol) as a pale yellow solid (0.191 g, 98% yield).
  • alkyne 8a (0.040 g, 0.3 mmol), iodobenzene 12b (0.106 g, 0.3 mmol), Na 2 CO 3 (0.003 g, 0.03 mmol), L-proline (0.0035 g, 0.003 mmol), NaN 3 (0.029 g, 0.45 mmol), sodium ascorbate (0.006 g, 0.03 mmol), CuSO 4 (1.0 M aqueous solution, 0.015 mL) and 1.0 mL mixed solvent of DMSO and H 2 O (9/1, VTV).
  • the reaction mixture was purged by nitrogen 10 min for deoxygen and then was heated to 65 0 C for 24 h.
  • alkyne 8b (0.145 g, 1.0 mmol)
  • iodobenzene 14a (0.264 g, 1.0 mmol)
  • tvans-N,N '-dimethyl- 1 ,2-cyclohexanediamine 0.024 mL, 0.15 mmol
  • Radioiodination Radioiodinated compounds [ 125 I]IOa and 10b, were prepared via iododestannylation reactions from the corresponding tributyltin precursors 11a and lib according to the method described previously. Hydrogen peroxide (50 ⁇ L, 3% w/v) was added to a mixture of 50 ⁇ L of the tributyltin precursor (4 ⁇ g/ ⁇ L EtOH), 50 ⁇ L of IN HCl and [ 125 I]NaI (1-5 mCi purchased from Perkin Elmer) in a sealed vial. The reaction was allowed to proceed for 10 min at room temperature and terminated by addition of 100 ⁇ L of sat. NaHSO 3 .
  • the no- carrier-added products were stored at -20 0 C up to 6 weeks for animal studies, homogenate binding and autoradiography studies.
  • Radiofluorination [ 18 F]Fluoride was produced by the JSW typeBC3015 cyclotron using 18 O(p,n) 18 F reaction and passed through a Sep-Pak Light QMA cartridge (Waters) as an aqueous solution in [ 18 O]- enriched water.
  • the cartridge was dried by airflow, and the 18 F activity was eluted with 1.3 mL of Kryptofix 222 (K222)/K 2 CO 3 solution (11 mg of K222 and 2.6 mg OfK 2 CO 3 in CH 3 CN/H 2 O 1.12/0.18).
  • K222 Kryptofix 222
  • K 2 CO 3 solution 11 mg of K222 and 2.6 mg OfK 2 CO 3 in CH 3 CN/H 2 O 1.12/0.18.
  • the solvent was removed at 120 0 C under an argon stream.
  • Example 3 Binding Studies AD postmortem brain tissues were obtained from University of Washington Alzheimer's
  • Ligand [ 125 I]2 with 2,200 Ci/mmol specific activity and greater than 95% radiochemical purity was prepared using the standard iododestannylation reaction, and purified by a simplified C-4 mini-column as described previously. Binding assays were carried out in 12 x 75 mm borosilicate glass tubes. For competition studies, the reaction mixture contained 50 DL of pooled AD brain homogenates (20-50 ⁇ g), 50 ⁇ l of [ 125 I]2 (0.04-0.06 nM diluted in PBS) and 50 ⁇ L of inhibitors (10 ⁇ 5 -10 ⁇ 10 M diluted serially in PBS containing 0.1 % bovine serum albumin) in a final volume of 1 mL.
  • Nonspecific binding was defined in the presence of 600 nM 2 in the same assay tubes.
  • the mixture was incubated at 37 0 C for 2 h and the bound and the free radioactivity were separated by vacuum filtration through Whatman GF/B filters using a Brandel M-24R cell harvester followed by 2 x 3 mL washes of PBS at room temperature. Filters containing the bound 125 I ligand were counted in a gamma counter (Packard 5000) with 70% counting efficiency. Under the assay conditions, the non-specifically bound fraction was less than 20% of the total radioactivity.
  • the results of inhibition experiments were subjected to nonlinear regression analysis using equilibrium binding data analysis which K 1 values were calculated.
  • radioiodinated and radio fluorinated ligands (0.06 nM for [ 125 I]probe and 0.5 nM for [ 18 F]probe to homogenates, prepared from the gray and white matters of AD and control brain tissues, were carried out as described above. Nonspecific binding was determined in the presence of 2 ⁇ M of the corresponding nonradioactive probes.
  • human macro- array brain sections from 6 confirmed AD cases and one control subject were assembled.
  • the presence and localization of plaques on the sections was confirmed with immunohistochemical staining with monoclonal A ⁇ antibody 4G8 (Sigma).
  • the frozen sections were incubated with [ 125 I] and [ 18 F]tracers (200,000-250,000 cpm/200 ⁇ L) for 1 h at room temperature.
  • the sections were then dipped in saturated lithium carbonate in 40% EtOH (two two-minute washes) and washed with 40% EtOH (one two-minute wash) followed by rinsing with water for 30 sec. After drying, the 125 I- or 18 F-labeled sections were exposed to Kodak Biomax MR film overnight.
  • [ 18 F]tracers Brain sections from AD subjects were obtained by freezing the brain in powdered dry ice and cut into 20 micrometer-thick sections. The sections were incubated with [ 18 F]tracers (200,000-250,000 cpm/200 ⁇ l) for 1 hr at room temperature. The sections were then dipped in saturated Li 2 CO3 in 40% EtOH (two two-minute washes) and washed with 40% EtOH (one two-minute wash) followed by rinsing with water for 30 sec. After drying, the 18 F-labeled sections were exposed to Kodak MR film overnight. The results are depicted in the film in Fig. 2.
  • [ 125 I]tracers To compare different probes using similar sections of human brain tissue, human macro-array brain sections from 6 confirmed AD cases and one control subject were assembled. The presence and localization of plaques on the sections was confirmed with immunohistochemical staining with monoclonal A ⁇ antibody 4G8 (Sigma). The sections were incubated with [ 125 I]tracers (200,000-250,000 cpm/200 ⁇ L) for 1 h at room temperature. The sections were then dipped in saturated Li 2 CO 3 in 40% EtOH (two two-minute washes) and washed with 40% EtOH (one two-minute wash) followed by rinsing with water for 30 sec. After drying, the 125 I-labeled sections were exposed to Kodak Biomax MR film overnight.
  • a macro-array block was constructed using postmortem human brain samples consisting of seven confirmed AD cases. After sectioning of this macro-array block, adjacent sections, which reflect a comparable pathophysiology, were used. In vitro film autoradiography was carried out using these novel 125 I or 18 F labeled diphenyltriazole probes. Among the probes examined, [ 18 F] 17a and [ 18 F] 17b exhibited the most distinctive A ⁇ plaque-labeling and a minimal level of background in the white matter areas of AD brain (Fig. 5). The labeling pattern was consistent with that observed by immunohistochemical labeling with an antibody (4G8) specific for A ⁇ (data not shown). In addition to plaque labeling, [ 125 I]IOa, displayed a significant white matter labeling (Fig.
  • Partition coefficients were measured by mixing the [ 125 I]or [ 18 F]tracer with 3 g each of 1- octanol and buffer (0.1 M phosphate, pH 7.4) in a test tube. The test tube was vortexed for 3 min at room temperature, followed by centrifugation for 5 min. Two weighed samples (0.5 g each) from the 1-octanol and buffer layers were counted in a well counter. The partition coefficient was determined by calculating the ratio of cpm/g of 1-octanol to that of buffer. Samples from the 1-octanol layer were re-partitioned until consistent partitions of coefficient values were obtained. The measurement was done in triplicate and repeated three times.
  • 123 I- 33 is a novel tracer that may be useful for SPECT imaging of amyloid- ⁇ (A ⁇ ) pathology (the chief constituent of amyloid plaques) in patients with cognitive impairment suspected to be due to Alzheimer's disease (AD). Because SPECT agents labeled with 123 I have long half- lives (approximately 13 hours) they can be prepared centrally, reducing the potential cost and variability involved with regional or on- site radiosynthesis. These inherent advantages, together with the excellent amyloid binding properties of 123 I- 33, provide a strong rationale for testing 123 I- 33 as an A ⁇ imaging agent.
  • a ⁇ amyloid- ⁇ pathology
  • AD Alzheimer's disease
  • Compound 33 shows high affinity and specific binding to amyloid plaques, as demonstrated by competitive binding studies using the known amyloid binding agent 125 I-IMPY (6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[l,2- ⁇ ]pyridine). In these experiments Compound 33 showed a Ki of 7.5 ⁇ 0.5 nM, comparable to other experimental amyloid imaging agents. 1 23 I- 33, when applied at tracer concentrations, specifically labeled A ⁇ plaques in sections from patients with pathologically confirmed AD.
  • Binding affinity of Compound 33 in AD brain homogenates as measured by inhibition of -125 I,- IMPY binding Postmortem brain tissue was obtained and neuropatho logical diagnosis was confirmed in accordance with the NIA-Reagan Institute Consensus Group criteria. Homogenates were then prepared from dissected gray matter, pooled in phosphate buffered saline and aliquoted into 1-ml portions (100 mg wet tissue/ml), which could be stored at -70° C for 3-6 months without loss of binding signal.
  • brain homogenates were incubated with 125 I-IMPY (0.04-0.06 nM diluted in phosphate buffered saline (PBS)) and test compound (10 ⁇ 5 - 10 "10 M diluted in PBS containing 0.1% bovine serum albumin (BSA)).
  • PBS phosphate buffered saline
  • BSA bovine serum albumin
  • Nonspecific binding was defined in the presence of IMPY (600 nM).
  • the bound and free radioactivity was separated by vacuum filtration followed by 2 x 3 ml washes of PBS. Filters containing the bound 125 I ligand were assayed in a gamma counter.
  • PIB JV-methyl[ rl l, C]2-4'-methylaminophenyl-6-hydroxybenzathiazole (Pittsburgh
  • FDDNP 2-( 1 - ⁇ 6-[(2-fluoroethyl)(methyl)amino]-2-naphthyl ⁇ ethylidene)malononitrile
  • Example 8 Biodistribution in ICR mice after an iv injection of [ 18 F]17b in 0.1% BSA/ ⁇ 1% ethanol in water (%dose/organ, avg of 3 mice ⁇ SD)
  • a compound of the present invention is tested in an established in- vitro immunoblot assay for its ability to inhibit the formation of A ⁇ oligomers and fibrils (Yang F, Liim GP, Begum AN et al. Curcumin inhibits formation of amyloid ⁇ oligomers and fibrils, binds plaques, and reduces amyloid in-vivo. J. Biol. Chem. 280:5892-5901, 2005). Curcumin, a natural molecule serves as positive control. Compounds of this invention are able to inhibit the aggregation A ⁇ in a manner similar to Curcumin at concentrations of 1-100 ⁇ M.

Abstract

L'invention concerne un procédé d'imagerie de dépôts amyloïdes et des composés diphényl-hétéroaryle et des procédés de fabrication de composés diphényl-hétéroaryle radiomarqués utiles dans l'imagerie de dépôts amyloïdes. La présente invention concerne également des composés et des procédés de fabrication de composés pour inhiber l'agrégation de protéines amyloïdes pour former des dépôts amyloïdes et un procédé de distribution d'un agent thérapeutique aux dépôts amyloïdes.
PCT/US2008/060710 2007-04-19 2008-04-18 Dérivés de diphényl-hétéroaryle et leur utilisation pour la liaison et l'imagerie de plaques amyloïdes WO2008131148A1 (fr)

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EP08746182A EP2144507A4 (fr) 2007-04-19 2008-04-18 Dérivés de diphényl-hétéroaryle et leur utilisation pour la liaison et l'imagerie de plaques amyloïdes

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KR102509289B1 (ko) 2014-12-15 2023-03-14 코르테바 애그리사이언스 엘엘씨 살충 유용성을 갖는 분자, 및 그와 관련된 중간체, 조성물 및 방법
WO2018206778A1 (fr) 2017-05-12 2018-11-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Dérivés de phényl-hétérocycle-phényle destinés à une utilisation dans le traitement ou la prévention d'un mélanome
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